Thyroid hormone is a well-known factor that is required for the development of the nervous system. Our study of the thyroid hormone receptor b gene (Thrb) identified a key role for a thyroid hormone receptor, TRb2, in the differentiation of retinal cone photoreceptors, the light-sensitive cells that mediate bright light vision and color vision. The findings indicated that in addition to the better-studied brain, the retina was an unexpectedly sensitive target of thyroid hormone. Color vision depends upon the differential expression in cone photoreceptors of opsin photopigments that confer sensitivity to different regions of the visible light spectrum. Most mammalian species are dichromatic and express opsins for sensitivity to medium-longer (M, green) or short (S, blue) wavelengths of light. Humans share this system but have trichromatic function because of a gene duplication that created another opsin gene for sensitivity to long wave (L, red) light. The mechanisms that pattern opsins are critically important for color vision but the underlying controls have remained largely elusive. Our study revealed that TRb2 is critical for the diversification of M and S opsin expression in cone sub-populations in mice. Deletion of TRb2 results in a loss of M opsin, revealing a key role for TRb2 in opsin patterning. The unexpected nature of this finding raises questions regarding the link between the endocrine and visual systems. Previously, in the study of thyroid disorders in humans or in mammalian model species, the possibility of color visual deficiencies had been largely overlooked. The project aims to investigate how TRb2 and thyroid hormone regulate cone development and to investigate which genes may cooperate with Thrb in the color visual system. Progress: 1. The role of thyroid hormone in modifying the timing and pattern of opsin expression in cone development in a mouse model. We investigate this key question to test the hypothesis that TRb2 and the hormonal ligand is important in modifying the development as well as the function and survival of cones. In addition, we continue to test the consequences of thyroid hormone imbalances at sensitive stages of retinal development to indicate possible cone defects that may potentially arise in developmental thyroid disorders. 2. Candidate factors that may cooperate with TRb2 in the development of cone photoreceptors include other transcription factors and the deiodinase enzymes that can activate or inactivate thyroid hormone in the retinal target tissues at key stages in development. We continue to investigate the underlying controls that direct the development of cone photoreceptors. These studies investigate the importance of mechanisms that both augment as well as constrain thyroid hormone action in the differentiation of specific cell types in immature tissues. 3. Investigation of the target genes that are regulated by TRb2 in retinal development. We continue our studies to identify the downstream genes that mediate thyroid hormone action in the retina. The identification of these critical target genes is expected to reveal insights into mechanisms of action of thyroid hormone and to identify new genes involved in photoreceptor differentiation and potentially also genes that underlie developmental or degenerative diseases of the retina.